16alpha-fluoromethyl compounds of the pregnane series and processes for the production thereof



United States Patent M 3,261,851 16a-FLUOROMETHY L COMPOUNDS OF THE PREG- NANE SERIES AND PROCESSES FOR THE PRO- DUCTION THEREOF Philip F. Beal Ill, Kalamazoo Township, Kalamazoo County, and John E. Pike, Kalamazoo, Mich, assignors to The Upjohn Company, Kalamazoo, Mich., a corporation of Delaware No Drawing. Filed Jan. 11, 1960, Ser. No. 1,454 28 Claims. (Cl. 260-3913) This invention relates to certain novel and therapeutically useful steroids and more particularly to (A) 1 6 a-fluoromethylhydrocortisone,

16a-fluorornethylcortisone,

16a-iluoromethyl-170;,21-dihydroXy-4-pregnene-3,2O-

dione,

l-dehydrod 6 wfiuoromethylhydrocortisone,

l-dehydro-lu-fiuoromethylcortisone,

16a-fluorornethyl-17a,21-dihydroxy-1,4-pregnadiene- 3,20-dione,

the Zea-methyl and Ga-methyl derivatives of these compounds and the 21-acylates thereof; (B)

and the ZI-acylates thereof; (C)

9a-halo-l6ewfluoromethylhydrocortisone, 9a-halo-16a-fiuoromethy1oortisone, 1-dehydro-9a-halo-l6a-fluoromethylhydrocortisone, 1-dehydro-9a-halo-16a-fluoromethylcortisone,

especially the 9a-fill01'0 compounds, the Zoe-methyl, 60cmethyl and 6u-fluoro derivatives of these compounds and the 21-acylates thereof; (D) the 21-fluoro and 21- desoxy compounds including the 17-acylates thereof which correspond otherwise to the compounds of Groups (A), (B) and (C), above, the 17,21-epoxy compounds corresponding otherwise to the compounds of Groups (A), (B) and (C), above, to novel steroid intermediates and to processes for the production thereof. The novel compounds of this invention, listed above under (A), (B), (C) and (D), can be represented by the following formulae:

3,261,851 Patented July 19, 1966 wherein R is hydrogen or the acyl radical of an organic carboXylic acid, preferably a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms, inclusive, R is hydrogen, fluorine, hydroXy or OAc in which Ac is the acyl radical defined as above, X is selected from the group consisting of the methylene radical CH the ,B-hydroxymethylene radical and the carbonyl radical C=O), Y is hydrogen or methyl, Y is hydrogen, methyl or fluorine, Z is hydrogen, fluorine, chlorine or bromine, and wherein when X is the methylene radical Z is limited to hydrogen. The above compounds are highly potent cortical hormones having anti-inflammatory, glucocorticoid, salt and water regulating, progestational, pituitary inhibiting and antianabolic activities with improved ratio of therapeutic activity to undesirable side-effects, e.g., gastrointestinal disturbances, edema, etc., known to exist with similar known physiologically active steroid compounds. Many of the higher molecular weight esters of the 21-hydroxy compounds, particularly those resistant to hydrolysis and/ or more insoluble in body fluids, provide compounds having more prolonged activity than the corresponding 21- hydroXy compounds. The above-named compounds are particularly useful in the treatment of various inflammatory conditions of the skin, eyes, respiratory tract and the bones and internal organs, contact dermatitis and allergic reactions, rheumatoid arthritis, and possess improved therapeutic ratios of anti-inflammatory activity to undesirable side-effects, compared to the corresponding compounds lacking the 16u-fluoromethyl group.

The novel 17,2l-epoxy compounds of Group (D) of this invention represented by the following formulae:

I Yr

wherein X Y, Y and Z have the meanings previously given and wherein when X is methylene Z is hydrogen, possess particularly marked diuretic activity in that they cause a loss of salt and water which makes them especially valuable in the treatment of cirrhosis of the liver, the nephrotic syndrome, and the treatment of eclampsia and pre-eclampsia.

Other compounds of this invention, as well as being useful as intermediates in the production of the above described compounds, also possess useful physiological activities, including anti-inflammatory, glucocorticoid, salt and water regulating, progestational, anti-fertility, muscle relaxing, central nervous system depressant and cardiotonic activities. Among these are the compounds represented by Formulae II, III, IIIa, IV, V, Va, VI, VIa, VII), IX, IXa, A-II, A-IV, AV, A-VI, AVIII, A -IX, A -II, A I II and A IV of the flow sheets set forth below.

The novel compounds of this invention and the therapeutically active intermediates can be prepared and administered to mammals, birds, humans and animals in a wide variety of oral, parenteral or topical dosage forms singly, or in admixture with other coacting compounds. They can be associated with a carrier which can be a solid material or a liquid in which the compound is dissolved, dispersed or suspended. The solid compositions can take the form of tablets, powder, capsules, pills or the like, preferably in unit dosage forms for simple administration or precise dosages. The liquid compositions can take the form of solutions, emulsions, suspensions, syrups or elixers. Pharmaceutical compositions and mixtures for topical use can take the form of ointments, lotions, jellies, creams, aqueous suspensions and the like.

The following starting materials for the processes of this invention are known in the art:

4, 16-pregnadiene-3 ,1 1,20-tr i0ne,

4, l 6-pregnadiene-3,20-dione, 3 acetoXy-16 pregnene-1 1,20-dione and 16a-cyan'o-3 ,fl-h'ydroiry-5-pregnen-20-one.

The other starting materials, i.e.,

2u-rnethyl-4,16-pregnadiene-3 ,1 1,20-trione, 6a-methyl-4,l6-pregnadiene-3,l 1,20-trione, 2oc-methyl-4,16-pregnadiene-3,20-dione and 6a-methyl-4, 1 6-pregnadiene-3,20-dione 0 Y-- Y" I R o 4- R o 4 are prepared from '2z-riietliyl-l l-ke'toprog'e'sterone, 6a-methyl-1 l-ketoprogesterone, 2a-methylprogesterone and 6a-methylprogesterone,

respectively, by catalytic reduction to produce the corresponding saturated A-ring compounds which can be converted to the Zea-methyl and 6w-methy1 starting materials listed above according to the procedures of U.S. Patent 2,794,814, as shown in Preparations 1-5 contained herein.

GROUP A The novel compounds of Group (A) of this invention are represented by the following formulae:

CHQOR; ([IHzORa 30 wherein R Y and X have the meanings previously 3 mediate compounds represented by Formulae IX and IXa are first prepared by one of three alternative procedures, Route 1 being generally preferred:

ROUTE 1 ROUTE 3 oflij-Cm QUE.

GROUP A 1 (3H3 (ll-0R o=o O H ]--OH2F Term IX I 02's and trans Y Y (IJHROAC (llHzoRa o=o CH ---0H 0: Tor-12F X l orm XI o= 0- I XII I cis and trans a! Y E 11110 OIHzOH i 3 t l ---o11 -OH E -CH2F 2 I a j Q i Y-- Y-- I t 2: i 0:. 0 XIII XIV i i Y i l JHioAc CIHIOH --OH --OH Term Term Y- Y I XVI I XV it it wherein Y, X and R have the meanings previously Route 1 given, Ac is the acyl radical of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms, inclusive, R is a lower alkylene radical containing from 1 to 8 carbon atoms, inclusive, and from 2 to 3 carbon atoms in the chain connecting the oxygen atoms, e.g., ethylene, trimethylene, 2,2-dimethyltrimethylene, n-propyl-ethylene, l,l,2,2,-tetramethylethylene, etc., R is hydrogen or methyl, R is an organic radical, particularly a hydrocarbon radical containing from one to ten carbon atoms, inclusive, e.g., methyl, ethyl, phenyl, tolyl, naphthyl, etc., R is a lower alkyl radical containing from 1 to 8 carbon atoms, inclusive, X is the methylene radical or the carbonyl radical and X is the methylene radical or the ,B-hydroxy-methylene radical.

enesulfon'ic acid, concentrated sulfuric acid, boron trifiuoride, etc., to produce the corresponding 3-cyclic ketal of the selected 4,16-pregnadiene (II). Ethylene glycol is the preferred ketalizing agent.

The B-ketalized 4,16-pregnadienes (II) thus produced are then treated with an alkali-metal cyanide, e.g., potassium cyanide or sodium cyanide, in the presence of a suitable solvent such as dioxane, methanol, ethanol, propanol, mixtures of these solvents and the like to produce the corresponding 3-ketalized 16a-cyano-4-pregnene (III), which can be hydrolyzed by methods known in the art, e.g., US. Patent 2,707,184 or 2,758,993 to produce the corresponding free 3-keto compound (Illa).

The 3-ketalized 16a-cyano-4-pregnenes (III) are then ketalized at the 20-position with a lower-alkylene uor fi-glycol, e.g., ethylene glycol in the presence of an acid catalyst, e.g., p-toluenesu-lfonic acid, sulfuric acid, etc. to produce the corresponding 3,20diketalized 16u-cyano-4- pregnene (IV). Reaction solvents which may be suitably employed include hydrocarbon solvents, halogenated hydrocarbons, ethers, and the like, e.g., benzene, xylene, hexane, chloroform, diethyl ether, tetrahydrofuran, dioxane, etc., or an excess of alkylene glycol can be used.

The 3,20-diketalized l6a-cyano-4-pregnenes (IV) thus obtained are then dissolved in an organic solvent, e.g., ethylene glycol, propylene glycol, dimethylsulfoxide, ethanol, tertiary amines such as pyridine and the like, and hydrolyzed with an aqueous base such as an aqueous alkali metal hydroxide solution, e.g., potassium hydroxide or sodium hydroxide, to give the corresponding 3,20- diketalized 16u-carboxy-4-pregnene (V), which can be esterified with ethereal diazomethane solution to produce the corresponding la-carbomethoxy compound (V).

The 3,20-diketalized l6m-carboxy or lu-carbomethoxy- 41pregnenes represented by Formula V, e.g., 16zx-C3lb0XY- 4-pregnene-3,11,20-trione 3,20-bis(alkylene ketal) or 1600- carboxy-4-pregnene-3,ZO-dione bis(alkylene ketal), the 20c and 6ot-methyl analogues thereof or the corresponding l6oc-carbomethoxy compounds, are then reduced with lithium aluminum hydride or other carboxyl reducing agent in an organic solvent or mixtures of organic solvents, e.g., ether, dioxane, tetrahydrofuran, benzene, toluene, and the like, to produce the corresponding 3,20-diketalized 16ahydroxymethyl-4-pregnene (VI), e.g., 1l/3-hydroxy-16ahydroxymethyl-4-pregnene-3,20-dione bis(alkylene ketal), la-hydroxymethyl 4 pregnene-3,20-dione bis(alkylene ketal) and the 20C- and oer-methyl analogues thereof. The ll-keto group when present in the starting material of this step are simultaneously reduced to the lLB-hydroxy group.

The 3,20-diketalized 1lfi-hydroxy-l6oc-hydroxymethyl- 4-pregnene-3,20-diones (VI) can be esterified by known methods, e.g., with a carboxylic acid anhydride in pyridine, to produce the corresponding 16u-acyloxymethyl compounds which can then be oxidized at the ll-position by known methods, e.g., with chromium trioxide in pyridine, chromic acid or sodium dichromate, chromic anhydride and dilute sulfuric acid, N-haloimide or N-haloamide in pyridine and the like to give the corresponding 3,20-diketalized l6a-acyloxymethyl-4 pregnene 3,11,20- triones (VIa) which on hydrolysis with aqueous base, e.g., aqueous sodium hydroxide, is productive of the corresponcling 3,20-diketalized 16et-hydroxymethyl-4-pregnene- 3,11,20-triones represented by Formula VIa.

The compounds of Formulae V, VI and VIa are useful anti-inflammatory, glucocorticoid, salt and water regulating, progestational, antifertility, central nervous system depressant and cardiotonic agents. These compounds can be hydrolyzed if desired by known methods for hydrolyzing cyclic ketal groups, e.g., with dilute aqueous acid in the same manner as described above for hydrolyzing the B-ketals, e.g., dilute aqueous acid, to give the free 3,20-ketones represented by Formulae Va and VIb, which have physiological activities similar to those of the parent compounds (VI) and (VIa), above.

The 3,20-diketalized 16ot-hydroxymethy1-4 -pregnenes (VI) and (VIa) are then reacted with an organic sulfonyl halide, e.g., p-toluenesulfonyl chloride, to yield the cor responding organic sulfonate ester of the 16tt-hydroxymethyl group (VII), e.g., the p-toluene sulfonate, which 'on fiuorination by means of potassium fluorosulfinate or an alkali metal fluoride, e.g., anhydrous potassium fluoride in the presence of a solvent, e.g., ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, and the like, at a temperature range between and 300 C. in an atmosphere of nitrogen gives the corresponding 3,20-diketalized 16ot-fiuoromethyl-4 pregnene (VIII).

The compounds of Formula VIII thus produced are then hydrolyzed by known methods of hydrolyzing cyclic ketal groups, e.g., dilute sulfuric acid, according to the method of US. Patents 2,707,184 or 2,758,993 for hydrolyzing 3-cyclic ke tals, to give corresponding 16afluoromethyl-4- pregnenes (IX), i.e., 11/3-hydroxy-16otfluoromethyl-4-pregnene-3,20-dione, l6u-fluoromethyl-4- pregnene-3,l1,20-trione, 16ot-fiuor0methyl 4 pregnene- 3,20-dione and the corresponding 2aand 6ot-methyl analogues thereof.

The llfl-hydroxy compounds (IX) thus produced are oxidized at the ll-position with chromium trioxide and pyridine or by other known methods, e.g., those previously described, to give the corresponding l6or-fluoromethyl4-pregnene-3,11,20-triones (IX), e.g.,

16a-fluoromethyl-4-pregnene-3,11,20-trione,

Za-methyl-I6ix-fluoromethyl-4-pregnene-3,1 1,20-trione,

and

6a-methyl-16a-fluoromethyl-4-pregnene-3,1 1,20-trione.

These compounds represented by Formula IX possess useful physiological activities, including anti-inflammatory, glucocorticoid, salt and water regulating, progestational, anti-fertility, cardiotonic and central nervous system depressant activities.

Route 2 Route 2 of this invention provides an alternate process for producing 16u-fluoromethyl-4-pregnene-3,l1,20-trione (IXa).

According to the process of Route 2, 3ot-hydroxy-l6- pregnene-11,20-dione or a S-acylate thereof (A-I), e.g., 3a-acetoxy-16-pregnene-11,20-dione, is treated with an alkali metal cyanide, e.g., potassium cyanide or sodium cyanide in a suitable solvent, e.g., those named in the cyanide reaction of Route 1, above, to produce 3ot-hydroxyl6ot-cyano-5a-pregnane-l1,20-dione (A-II), which is then ketalized at the 20-position with a lower alkylene aor B-glycol in the manner described in Route 1 for producing the compounds of Formula IV, to produce 3a-hydroxy- 16ot-cyano-5fl-pregnane-1l,20dione 20 alkylene ketal (A-III). Compound A1l1 is then hydrolyzed with an aqueous alkali-metal hydroxide, e.g., potassium or sodium hydroxide in a suitable organic solvent, e.g., ethylene glycol, to give 3a-llydIOXY-16oa carboxy 513 pregnanc- 1l,20-dione 20-alkylene ketal which is then esterified with ethereal diazomethane to give 3fi-hydroxy-l6a-carbometl1oxy-5,8-pregnane ZO-alkylene ketal (A-IV). This compound is then oxidized, e.g., with an N-haloamide or an N-haloimide in pyridine, with chromic anhydride or chromium trioxide and dilute sulfuric acid in acetone or methylene chloride, with sodium dichromate in glacial acetic acid, or other known oxidizing agents to produce 16a-carbomethoxy-Sfl-pregnane-B,11,20-trione 20-alkylene ketal which is then ketalized at the 3-position according to the procedures described in Route 1 for ketalizing the compounds of Formula III to produce 16a-c-arbomethoxy- 5fl-pregnane 3,11,20 trione, 3,20 bis(alkylene ketal) (A-V). This compound is then reduced with lithium aluminum hydride or other carboxyl reducing agent in the same manner as described in Route 1, above, to give 11 fl-hydroxy-lot-hydroxymethyl-i fl-pregnane-3,20 dione bis(alkylene ketal) (A-VI). This compound (A-VI) can be hydrolyzed by acid, e.g., dilute aqueous sulfuric acid in acetone to give 1lfl-hydroxy-IGa-hydroxymethylfi-pregnane-3,20-dione. The l6a-hydroxymethyl group of A-VI is then reacted with an organic sulfonyl halide, e.g., p-toluenesulfonyl chloride, to give the corresponding organic sulfonate of the l6a-hydroxymethyl derivative (A-VII), e.g., the p-toluenesulfonate, which is then fluorinated by means of an alkali metal fluoride, e.g., anhydrous potassium fluoride, to produce 11t3-hydroxy-16afluoromethyl 5p3-pregane-3,20-dione bis(alkylene ketal) (A-VIII). This compound is then oxidized by known methods for oxidizing the ll-position of steroids, e.g., hydrocortisone to cortisone, e.g., using chromium trioxide in pyridine, to produce to corresponding 11-keto compound which is then hydrolyzed under acid conditions to remove the ketal groups, e.g., dilute aqueous sulfuric acid, to give 16a-fiuoromethyl-5B-pregnane-3,11,20-trione- (A-IX). This compound is then treated with a halogenating agent, e.g., a hypohalous acid, a mineral acid with a hypochlorite, such as t-butylhypochlorite, N-bromoacetamide, N-bromosuccinimide, N-chloroacetarnide, N-chlorosuccinimide and the like, to give the corresponding 4-halo-1Ga-iiuoromethyl-Sfi-pregnane 3,11,20- trione. The 4-halo compound thus obtained can be converted to the corresponding A compound according to the procedure disclosed in U.S. Patent 2,794,814, e.g., by treatment with semicarbazide hydrochloride followed by pyruvic acid, to give 16cc fluoromethyl 4 pregnene- 3,11,20-trione (IXa).

Route 3 Route 3 of this invention provides another alternate procedure for producing l6a-fiuoromethyl-4 pregnene- 3,11,20-trione (IXa) and 3fi-hydroxy-16ot-fluoromethyl- 5-pregnen-20-one (A'IV) which is used as starting material for production of the 6oc-flu010 compounds of Group B of this invention.

According to the process of Route 3, 3fl-hydroxy-16acyano-S-pregnen-ZO-one is ketalized at the 20-position accord-ing to the method previously described in Routes 1 and 2 for ketalizing compounds of Formula III and A-II, to produce the corresponding 3,8-hydroXy-16a-cyano-5- pregnen-ZO-one 20-alkylene ketal (A-II), which is then hydrolyzed with an aqueous alkali-metal hydroxide, e.g., potassium or sodium hydroxide to give 3fl-hydroxy-l6acarboxy-S-pregnen-ZO-one 20-alkylene ketal (A'-III).

Compound A'III is then treated with dihydropyran in the presence of an acid catalyst, e.g., p-toluenesulfonic acid, concentrated sulfuric acid, benzenesulfonic acid, anhydrous hydrogen chloride and the like, to produce the corresponding 3 tetrahydropyranyloxy 16a carboxy-S- pregnen-ZO-one 20-alkylene ketal tetrahydropyranyl ester. Reaction solvents which may be suitably employed in the dihydropyran reaction include benzene, toluene, Skellysolve B hexanes, xylene, diethyl ether, dioxane, chloroform, tetrahydrofuran and the like.

The tetrahydropyranyl ester is then reduced with lithium aluminum hydride or other carboxyl reducing agent in the same manner as described in Route 1, above, for reducing the compounds of Formula V to produce the corresponding 3-tetrahydropyranyloxy 16cc hydroxy-methyl- 5-pregnen-20-one 20alkylene ketal which is then reacted with an organic sulfonyl halide, e.g., p-toluenesulfonyl chloride to produce the corresponding organic sulfonate of the 16a-hydroxymethyl group, e.g., p-toluenesulfonate, which on fiuorination by means of an alkali metal fluoride, e.g., anhydrous potassium fluoride gives the corresponding B-tetrahydropyranyloxy 16u-fiuoromethyl-5-pregnen- 20-one 20-alkylene ketal. This compound is then hydrolyzed with dilute aqueous acid, e.g., sulfuric acid to give 3fl-hydroxy-l 6a-fluoromethyl-S-pregnen-ZO-one (A'IV) This compound (A'IV) is then oxidized (Oppenauer oxidation) with a ketone, e.g., acetone or cyclohexanone and an aluminum alkoxide, e.g., aluminum isopropoxide, to give 16a-fluoromethyl-4-pregnene-3,20-dione (A'V). This compound is then oxygenated at the 11-position by microbiological conversion, according to the procedure of U.S. Patent 2,735,800 for converting progesterone to hydroxyprogesterone, to produce 11a-hydroxy-16a-fluoromethyl-4-p-regnene-3,20-dione (A'VI), Which is then oxidized at the ll-position by known methods, e.g., chromium trioxide and sulfuric acid, to produce 1606-flllOIO- methyl-4-pregnene-3,1 1,20-trione (IXa) The compounds of Formula IX, i.e., 16a-fluoromethyl- 4-pregnene-3 ,20-dione, 16a-fluoromethyl-4-pregnene-3 ,11, 20-trione, 1lfi-hydroxy-1-6a-fluoromethyl-4-pregnene-3,20- dione, and the corresponding 2a-methyl and 6oc-methyl analogues, are converted to the corresponding cis and trans 4,17(20)-pregnadien-2l-oic acid alkyl esters (X) according to the methods described in U.S. Patent 2,790,814. The compounds of Formula X are then converted to their 3-ena'mines, reduced with an alkali-metal aluminum hydride, and hydrolyzed to remove the 3-enamine group, as described in U.S. Patent 2,781,343 to produce the 21- hydroxy compounds of Formula XI, i.e., cis and trans 11fi,21-dihydroxy-16u-fluoromethyl- 4, 17 (20 -pregnadien- 3-one, 16a-fluoromethyl-2 1-hydroxy-4, 17 (20) -pregnadien- 3-one, and the 2amethyl and 6ot-methyl analogues thereof. The 11-keto group when present is simultaneously reduced to the 11 B-hydroxy group. The 21-free alcohols (XI) thus produced are esterified with an anhydride or acid halide of an organic carboxylic acid preferably a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms inclusive, including dicarboxylic acids, in pyridine or with an acid, e.g., formic, or an ester in the presence of an acid catalyst to produce the corresponding 21- acylate (XI).

The 21-acylates preferably the 2l-acetates of Formula XI are then oxidatively hydroxylated with osmium tetroxide and an amine oxide peroxide according to the procedure of U.S. Patent 2,769,825 or with an organic polyvalent iodo oxide, e.g., phenyliodoso acetate, according to the procedure of U.S. Patent 2,875,217 to give the compounds of Formula XII.

The llB-hydroxy compounds of Formula XII, e.g., 16afiuoromethylhydrocortisone 21-acylate and the corresponding Za-methyl and oat-methyl analogues are oxidized in accordance with known methods for oxidizing hydrocortisone 21-acetate to cortisone 21-acetate, e.g., chromic anhydride and acetic acid, chromium trioxide and sulfuric acid, N-haloimides or N-haloamides, etc., to produce the corresponding ll-keto compounds of Formula XIII.

The compounds of Formulae XII and XIII are then converted to the corresponding 21-free alcohols (XIV) by hydrolysis in accordance with known methods for hydrolyzing hydrocortisone 21-acylates to hydrocortisone, e.g., sodium or potassium bicarbonate in aqueous alcohol, in an oxygen-free atmosphere.

The compounds of Formula XIV are dehydrogenated at the 1,2-position by fermentative or chemical dehydrogenation to give the corresponding l-dehydro compounds of Formula XV. Fermen-tative dehydrogenation comprises the use of microorganisms such as Septomyxa, Corynebacterium, Fusarium, and the like, under fermentation conditions well known in the art (e.g., U.S. 2,602,769, 2,902,410 or 2,902,411). Where Septomyxa is used to effect the dehydrogenation it is found to be advantageous to use with the substrate and medium a steroid promoter, such as progesterone, 3-ketobisnor-4-cholen-2-al, 3-ketobisnorcholenic acid, 115,21 dihydroxy 1,4,17(20)-pregnatrien-S-one, and the like. The free alcohols are usually employed as starting material for the fermentative dehydrogenation process. However, 21-acylates of Formulae XII and XIII can be used. In these cases the 21- ester group is generally saponified during the fermentation process giving the corresponding 21-free alcohol represented by Formula XV. Chemical dehydrogenation can be carried out with selenium dioxide according to procedures well known in the art [e.g., Meystre et al., Helv. Chim. Acta, 39, 734 (1956)]. The 21-acylates of For- 17 mulae XII andXIII are generally preferred as starting material in the chemical dehydrogenation reaction giving the corresponding 21-acylate represented by Formula XVI. The 2l-acylate thus obtained can be saponified, if desired, by methods known in the art to give the corresponding 21-free alcohol (XV).

The compounds of Formulae XIV and XV are reesterified to the corresponding 21-acylates by reaction with the selected acylating agent. This reaction can be performed under the esterification conditions known in the art, e.g., by the reaction of XIV or XV with the selected acid chloride or acid bromide or the anhydride of an organic carboxylic acid, or by reaction with the selected acid in the presence of an esterification catalyst, for example, p-toluenesulfonyl chloride, trifluoroacetic anhydride, .p-toluenesulfonic acid, trifiuoroacetic acid, sulfuric acid, and the like, or with an ester under ester exchange reaction conditions. Compounds thus produced include those wherein Ac is the acyl radical of a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms, inclusive, e.g., the acids listed in Example 36A.

* AW m1); Mir ii 18 GROUP B wherein R and X have the same meanings: as previously given.

The processes for the production of the compounds of Group B of the present invention are illustratively represented by the following reaction scheme:

C Ha

: f 0 i H3 H3 a 0: 0:0 5 --0H '---0H E Term ]--O 3 i i A00 A00 5 5 I XX v 5 I XXI i '0 116 F x l ornBr 1m C: 0 0 -0H Toms Tenn i i HO H0 XXIII 5 XXII I no no F WIT . XXV l I 1-16 F 116 1 ([lHzORs CIHJORB HO Term" --OH2F XXVII I XXVI f a 1 l e N l i (llI-IzORa onion i i e i i ---011 -OI-I i o=y l: ]--CII;F Term I i i o: XXVIII I XXIX 1' 1' i E l T i x, E .z' L ornoAc or I wherein X is the methylene radical, the carbonyl radical or the hydroxymethylene radical and wherein Ac and 60 R have the same meanings as previously given. In this application the wavy line appearing at the ll-position denotes either the a or ,8 configuration or mixtures thereof.

The process of preparing the compounds of Group B of the present invention involves esterifying 3 3-hydroxy- 16a-fluoromethyl-5-pregnen-20-one (A'IV), e.g., with acetic anhydride and a strong acid catalyst, to produce 3,8,20-dihydroxy-16a-fluoromethyl-5,17(20) pregnadiene 3,20-diacetate (XVII) which is then converted, preferably without isolation, with a peracid', e'.g., peracetic or perbenzoic acid, to 3 8,20-dihydroxy-5a,6a,17a,2()-diepoxy-l6ot-fluoromethylpregnane 3,20-diacetate (XVIII), in exactly the manner that pregnenolone has been converted to the diepoxide of its 3,20-diacetate. This com- XXX pound is hydrolyzed, preferably without isolation, with aqueous base, e.g., sodium hydroxide or potassium hydroxide, to produce 3fl,17a-dihydroxy-5a,6a-epoxy-16afluoromethylpregnan-ZO-one (XIX). A by-product in the above series of reactions is the corresponding 5,8,6fiepoxide. This compound is desirably separated from the desired 5a,6a-epoxide, e.g., by fractional crystallization of XVIII or by converting the mixture of XIX and the corresponding 55,6/3-epoxide to a 3-acylate thereof (XX), e.g., formate, acetate, trifluoro acetate, benzoate, preferably a lower-hydrocarbonacylate, and separating these epoxides, e.g., by known methods of chromotography or fractional crystallization. The epoxide opening step is carried out according to the procedure of US. Patent 2,838,497, i.e., 3/3,l7a-dihyClIOXy-5a,6ocepoxy-16a-fiuoromethylpregnan-20-one (XIX) or a 3- acylate thereof (XX) is converted with anhydrous hydrogen fluoride in chloroform or methylene chloride in the presence of tetrahydrofuran at 60 C. to +20 C., or aqueous hydrogen fluoride, e.g., at to 30 C., to 3fi,5a,17a-trihydroxy-6,B-fiuoro 16oz fluoromethylpregnan-20-one (XXII) and 3,8,5tx,l7a-trihydroxy-6/i-fluoro- 16a-fluoromethylpregnan-20-one 3-acylate (XXI), respectively. The latter compound (XXI) is hydrolyzed with aqueous acid, e.g., hydrochloric, sulfuric or boron trifluoride in methanol, to produce the former compound (XXII), which is then brominated, e.g., with a molar equivalent of bromine in chloroform or acetic acid to produce 3l3,5oc,17oc trihydroxy-6B-fiuorod6ot-fluoromethyl-2l-bromopregnan-20-one (XXIII). Reaction of this compound with alkali-metal lower-hydrocarbon acylate, e.g., potassium acetate, sodium acetate, sodium formate, sodium propionate, potassium fl'cyclopentylpropionate, sodium benzoate, etc., is productive of 3/3,5a,17oz,21-tl11 hydroxy-6a-fiuoro-16a-fiuoromethylpregnan 20 one-21- acylate (XXIV). Oxidation of this compound with sodium dichromate in glacial acetic acid, chromic anhydride and aqueous sulfuric acid in acetone or methylene chloride or an N-haloamide or N-haloimide in pyridine is productive of 5a,l7a,2l-trihydroxy 6B fiuoro-16afiuoromethylpregnane-3,20-dione 21-acylate (XXV). Reaction of this compound with acid, e.g., hydrogen chloride in CHCl preferably in the presence of less than 2% of a lower-alkanol, e.g., ethanol or t-butyl alcohol, is productive of 6a-fluoro-16a-fluoromethyl-l7a,2l-dihydroxy-4-pregnene-3,20-dione 2l-acylate (XXVI), which is hydrolyzed with base according to known procedures, e.g., the hydrolysis of hydrocortisone ZI-acylates to hydrocortisone, to give 6a-fluoro-16a-fluoromethyl-17tx,21- dihydroxy-4-pregnene-3,ZO-dione (XXVI).

The 6rx-flt10r0 16cc fluoromethyl-17u,21-dihydroxy-4- pregnene-3,20-dione or a ZI-acylate thereof (XXVI) is then converted to 6a-fluoro-16a-fiuoromethylhydrocortisome and the 21-acylate thereof (XXVII), by reaction with an llfi-hydroxylating species of fungus, e.g., Cunninghamella blakesleeana, Curvularia lunata, Trz'chothecium roseum, etc., according to procedures Well known in the art, e.g., U.S. Patent 2,602,769. The free alcohol (XXVI) is usually employed as the starting material in the fermentation reaction, however the 21-acylates (XXVI) can be used. In these cases the 2l-ester is generally saponified during the fermentation giving the 21- free alcohol (XXVII), which can be reesterified by known 2l-esterification methods.

Alternatively 60 fiuoro-l6ec-fluoromethyl-l7a,2l-dihydroxy-4-pregnene-3,20-dione or a 2'1-acylate thereof (XXVI) can be converted to 6ix-fluoro-l1a,l7a,21-trihydroxy-l6a-fiuoromethyl-4-pregnene-3,20-dione or a 21- acylate thereof (XXVII) by reaction with an lla-hydroxylating species of fungus, according to the procedure of U.S. Patent 2,735,800 for converting 17a,2l-dihydroxy- 4-pregnene-3,20-dione to lla,17u,2l-trihydroxy-4-pregnene-3,20-dione. The free alcohol (XXVI) is usually employed as the starting material, however the 2l-acylates can be used. In these cases the 2l-ester is generally saponified during the fermentation giving the free alcohol (XXVII), which can be reesterified at the 21-posi- 22 tion by known selective ZI-esterification methods, e.g., US. Patent 2,735,800.

The 6a-fluoro 16a fluoromethylhydrocortisone, 6afluoro-lla,17u,2l-trihydroxy 16a fluoromethyl-4-pregnene-3,20-dione or the 2l-acylates thereof (XXVII) are then oxidized to 6a-fluoro-l6a-fluoromethylcortisone or the corresponding ZI-acylate, respectively, in accordance with known methods for oxidizing the 11,8-hydroxy group to the 11-keto group hereinbefore described, e.g., N- bromacetamide or chromic acid.

The compounds of Formulae XXVI, XXVII and XXVIII are dehydrogenated at the 1,2-position by fermentative or chemical dehydrogenation. Fermentative dehydrogenation comprises the use of microorganisms such as Septomyxa, Corynebacten'um, Fusarium, and the like, under fermentation conditions well known in the art (e.g., US. 2,602,769, 2,902,410 and 2,902,411). Where Septomyxa is used to effect the dehydrogenation it is found to be advantageous to use with the substrate and medium a steroid promoter. The free alcohols are usually employed as starting material for the fermentative dehydrogenation process. However, the corresponding 21-acylates can be used. In these cases the 2l-ester group is generally saponified during the fermation process given the corresponding free alcohol. Chemical dehydrogenation can be carried out with selenium dioxide according to procedures well known in the ant [e.g. Meystre et al., I-Ielv. Chim. Acta, 39, 734 (1956)]. The 2l-acylates are generally preferred as starting material in the chemical dehydrogenation reaction giving the corresponding compounds of Formula XXX. The 21-acylates thus obtained can be saponified, if desired, by methods known in the art to give the corresponding ZI-free alcohols.

GROUP C The novel 9u-halocortisones and 21-acylates thereof of Group C of this invention are represented by the follow ing formulae:

XXXVII *XXXI is combined from Formulae XII, XVI, XXVII and XXX.

wherein X, Y, Y Z and Ac have the same meanings as previously given and Z is a halogen having an atomic weight from 35 to 127, inclusive, i.e., bromine, chlorine or iodine. The dotted line appearing in Formulae XXXI to XXXVII represents a A double bond which may or may not be present.

The 9a-halo compounds of Group C of this invention are prepared according to the procedure of US. Patent 2,852,511 as follows: dehydrating 16tx-fiuoromethylhydrocortisone 21-acylate (XXXI) or the corresponding 20:- methyl, 6a-methyl or 6oc-fl110l'0 analogues thereof, or 1- dehydro 16oz fiuoromethylhydrocortisone 21 acylate (XXXI) or the corresponding Z-methyl, 6a-methyl or 60:- fluoro analogues thereof, represented by Formula XXXI, with an N-haloamide, e.g., N-bromoacetamide in pyridine followed by anhydrous sulfur dioxide produces the corresponding A compounds (XXXII), i.e., l6a-fluoromethyl 170:,21 dihydroxy 4,9(1l)-pregnadiene-3,20- dione 2l-acylate, the Zea-methyl, 6a-methyl and 6a-fiuoro analogues thereof and the corresponding 1,4-pregnadienes, respectively. Addition of a hypohalous acid, i.e., hypobromous, hypochlorous or hypoiodous, to these latter compounds produces the corresponding 9a-halo corn- 2 pounds (XXXIII), i.e., 9ut-halo-l6u-fluoromethylhydrocortisone 21 acylate, the 20c methyl, 60c methyl and 6a-fluoro analogues thereof and the corresponding l-dehydro compounds, respectively, which by treatment with base, e.g., anhydrous potassium acetate, yield the corresponding epoxy compounds (XXXIV), i.e., 16a-fiuoromethyl 95,11B-epoxy-l7a,2l-dihydroxy-4-pregnene-3,20- dione 21-acylate, the Zea-methyl, 6a-methyl and 6OL-fiuOIO analogues thereof and the corresponding 1,4-pregnadienes, respectively. Treatment of these epoxy compounds with hydrogen fluoride or other hydrogen fluoride releasing agents produces the corresponding 90c-fluOIO compounds (XXXV), i.e., 9u-fluoro-l6tt-fiuoromethylhydrocortisone 21-acylate, the 2a-methyl, 6m-methyl and 6afluoro analogues thereof and the corresponding l-dehydro compounds, respectively. Oxidation of the llfl-hydroxy compounds represented by Formulae XXXIII and XXXV, preferably the 2l-acetates with, e.g., chromic acid in acetic acid provides the corresponding ll-keto compounds (XXXVI), e.g., 9a-fiuoro-l6a-fiuoromethyl-coitisone 21- acylate, the Zea-methyl, 606-1'116thY1 and 6ot-fiuoro analogues thereof, the corresponding l-dehydro compounds and the other corresponding 9OL-bI'OIT10, 9a-chloro and 9a-iodo llketo compounds represented by Formula XXXVI. Hydrolysis of the 21-esters of Formulae XXXIII, XXXV and XXXVI with a base, e.g., aqueous sodium hydroxide or sodium bicarbonate, provides the corresponding free 2l-alcohols represented collectively by Formula XXXVII, e.g.,

9tx-fiuoro-16a-fiuoromethylhydrocortisone,

the corresponding 2u-methyl, 60t-1Tl6thyl and 6ot-fluoro analogues thereof and the other corresponding 9u-bromo, 9a-chloro and 9a-iodo 21-free alcohols represented by Formula XXXV II.

The 2l-free alcohols (XXXVII) thus produced can be reesterified by known Zl-acylation methods to produce the corresponding 21-acylates wherein the acyl radical is that of an organic carboxylic acid, preferably that of a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms, inclusive, e.g., those acids named in Example 36A.

Alternatively the A -cornpounds represented by Formula XXXVII and the Zl-acylates thereof can be converted to the cor-responding A -compounds by known fermentative or chemical 1,2-dehydrogenation procedures herein before described in Groups A and B, above, e.g., using Septomyxa (US. Patents 2,902,410 and 2,902,411) or selenium dioxide.

GROUP D The novel 21-desoxy and 2l-fluoro compounds of Group D and the l7-acylates thereof are represented by the following formulae:

wherein R Y, Y X and Z have the same meanings as previously given, R is hydrogen or fluorine and wherein when X is the methylene radical Z is hydrogen.

The processes for the production of the compounds of Group D of this invention are illustrativelly represented by the following reaction scheme:

CHzOH (l /112080 112 (3 0 (3 0 --0H --OII k6 U 1? -OH2F XXXVIII XXXIX in in (EH21 (.[TH F (1:0 0 0 IM ---or-I "CIDF X2 "CIHF XL XLI' in $H5 (BT12 0:0 0:0 0 OH i X2 "CYDF -CTI2F J XLIV XLII (Elia $13121 :0 0 0 A La OAC X2 "CH2F --CH2F I XLV XLIII in *Formula XXXVIII is combined from Formulae XIV, XV, XXVI, XXVII, XXVIII, XXIX, and XXXVII.

27 wherein Ac, R Y, Y X and Z have the same meanings as previously given and wherein when X is the methylene radical Z is limited to hydrogen. The dotted line appearing in Formulae XXXVIII to XLV represents a A double bond which may or may not be present.

The 2l-fiuor0 compounds of Group D of the invention are prepared according to the procedure of U.S. Patent 2,838,535 or 2,838,543, i.e., by treating the compounds of Formula XXXVIII with an organic sulfonyl halide such as methanesulfonyl chloride, toluenesulfonyl chloride, toluenesulfionyl bromide benzenesulfonyl chloride, naphthylenesulfonyl chloride, or the like, to obtain the corresponding 2l-sulfonate (XXXIX), treating the thusproduced 21-alkyl or aryl sulfonate (XXXIX) with. sodium iodide in acetone solution to obtain the corresponding 21-iod-o compounds (XL), treating the thus-obtained 21- iodo compounds with silver fluoride, preferably in acetonitrile solution to obtain the corresponding 21-fiuoro compounds (XLI). Alternatively, the 2lsulfonate (XXXIX), preferably the 21-methylsulf-onate, can be treated directly with potassium fluoride in dimet-hyl sulfoxide, to produce the 21-fluoro compounds directly. When this alternate process is employed, the corresponding 17,21-epoxy compounds (XLII) are concomitantly produced.

The ZI-un-substituted compounds of the present invention are prepared according to the procedure of U.S. Patent 2,838,541 or 2,838,542, i.e., by treating a 21-iodo compound (XL), with a reducing agent such as sodium thiosulfat-e, sodium bisulfite, potassium b-isulfite, or the like, in an aqueous organic solvent mixture, to obtain the corresponding 21-unsubstituted compound (XLIV).

Alternatively 16a fluoromethyl 17a hydroxy 4- pregnene-3,20-dione (XLIV), is prepared by treating the selected 3,8,170: dihydroxy 50:,60: epoxy-16a fluoromethylpregnan-ZO-one-S-acylate(XX) with zinc and sodium iodide in acetic acid to produce the corresponding 3,8,170: dihydroxy 16cc fluoromethyl 5 pregnen 20- one B-acylate which is then hydrolyzed by known methods, e.g., aqueous sodium hydroxide to give the free alcohol, 3,8,170c dihydroxy 16a fluoromethyl 5 pregnen-20-one, which is then oxidized (Oppenauer oxidation) with an aluminum alkoxide, e.g., aluminum isopropoxide to give 16u-fiuoromethyl-17a-hydroxy-4-pregnene-3,20-dione (XLIV). Preferably the 3fl,17a-dihydroxy-16a-fiuoromethyl-5-pregnen-ZO-one is dissolved in acetone and oxidized with aqueous chromic acid in the presence of sulfuric acid and then isomerized with, e.g., oxalic acid or dilute alkali to give 16u-fluoromethyl-17othydroxy-4-pregnene-3,20-dione (XLIV).

The compounds of Formulae XLI and XLIV are esterified at the 17-position according to known 17-esterification methods, e. g., an acid anhydride in the presence of an esterification catalyst, e.g., acetic anhydride and p-toluenesulfonic acid, to produce the corresponding 17- acylates (XLIII and XLV), respectively, wherein the acyl radical is that of an organic carboxylic acid, preferably that of a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms, inclusive, e.g., those acids listed in Example 36Av Alternatively the 9a-halo compounds represented by Formulae XLI and XLIV wherein X is ,G-hydroxy and Z is halogen can be prepared by converting the corresponding compounds of Formulae XLI and XLIV, respectively, wherein Z is hydrogen to the corresponding 90:.- halo compounds via the 9(11)-dehydro compound in the manner described hereinbefore in Group C above.

Alternatively the A -compounds of Formulae XLI and XLIV, and the 17-acylates thereof, (XLIII) and (XLV), can be converted to the corresponding A -compounds by known fermentative or, preferably, chemical 1,2-dehydrogenation procedures hereinbefore described in Groups A and B, above, e.g., using Septomyxa (U.S. Patents 2,902,410 and 2,902,411) or selenium dioxide.

Alternatively, the compounds of. Formulae XLI and 28 XLIV and the ZI-acylates thereof (XLIII and XLV) wherein X is the carbonyl radical can be prepared by oxidation of the corresponding 11,6-hydroxy compounds by methods known in the art for the oxidation of hydrocortisone acetate to cortisone acetate, e.g., chromic acid, N-bromoacetamide and the like.

PREPARATION 1 6 a-me thy lpregnan'e-3 ,1 1 ,ZO-trione A mixture containing 0.5 g. of 6a-methyl-11-ketoprogesterone, t-butyl alcohol and mg. of 5% palladium on charcoal as a catalyst is hydrogenated at a pressure of about 15 psi. (guage) in a Parr hydrogenation apparatus. When the uptake of hydrogen ceases, the reaction mixture is filtered to remove the catalyst and concentrated. The residue thus obtained is recrystallized from acetone: Skellysolve B hexanes to give 6ot-methylpregnane-3,l1,20- trione, a light colored crystalline solid. Alternatively, if desired, the residue may be purified by chromatography.

In the same manner substituting as the starting steroid in Preparation 1, 2oz methyl -11 ketoprogesterone, 6u-methylprogesterone or Za-methylprogesterone, there is thus produced, 2a-rnethylpregnane-3,11,20-trione, 6amethylpregnane-3,20-dione and 2a-methylpregnane-3,20- dione, respectively.

PREPARATION 2 3,20-diaceZ0xy-6a-methyl-3J 7 (20)-pregnadiene-1 I -one A mixture of 300 mg. of 6a-methylpregnane-3,11,20- trione, 15 ml. of acetic anhydride and mg. of p-toluene sulfonic acid monohydrate is heated to boiling and allowed to distill slowly until most of the excess acetic anhydride is distilled. The last traces of excess acetic anhydride are removed under vacuum, and the resulting residue is cooled and dissolved in ether. The ether solution is washed with cold 10% aqueous sodium bicarbonate solution and dried over sodium sulfate. The ether is then evaporated to give a residue of 3,20-diacetoxy-6umethyl-3 ,17(20)-pregnadiene-11-one.

PREPARATION 3 4,17ix-dibrom0-6a-methylpregnane-3,11,20-trione mg. of 3,20-diacetoxy-6a-methyl-3,l7(20)-pregnadien-ll-one is dissolved in t-butyl alcohol and treated with a solution of 125 mg. of N-bromosuccinimide in 15 ml. of t-butyl alcohol and with 5 ml. of 1 N sulfuric acid. The mixture is allowed to stand at room temperature until the reaction is complete. The reaction mixture is then concentrated in vacuo, diluted with water and the resulting product collected on a filter. Recrystallization from alcohol gives 4,17a-dibromo-6a-methylpregnane-3,11,20-trione, a light colored crystalline solid.

PREPARATION 4 6u-methyl-17otbr0m0-4-pregnene-3,11,20-tri0ne A solution of 1 millimole of 4,17a dibromo-6a-methylpregnane-3,l1-20-trione dissolved in dioxane is admixed with 2.5 ml. of an aqueous solution containing 2 millimoles of semicarbazide and 2 millimoles of anhydrous sodium acetate. The mixture is stirred overnight at room temperature and thereafter a solution of 0.52 g. of pyruvic acid in 5 ml. of water is added. The reaction mixture is then heated to about 70 C. for a period of about 3 hours, cooled and poured into water. The thus produced 61xmethyl-l7a-bromo-4-pregnene-3,11,20-trione is extracted from the aqueous mixture with methylene chloride. The extracts are combined, washed with 1% aqueous sodium hydroxide solution, and water until the wash water is neutral, dried over anhydrous sodium sulfate and concentrated. The residue is purified by chromatography over Florisil (synthetic magnesium silicate) and recrystallized from acetone:Skellysolve B hexanes to give 6a-m'ethyll7a-bromo-4-pregnene-3,l1,20-trione, a light colored crystalline solid.

PREPARATION 5 6ot-methyl-4J 6-pregnadieize-3,11,20-tri0rze 1.0 g. of Got-methyl-17a-bromo-4-pregnene-3,l1,20- trione is dissolved in dry pyridine and heated under reflux for a period of about 24 hours. The pyridine is then removed by distillation at reduced pressure and the residue thus obtained is dissolved in benzene. Water is then added to the benzene solution and the layers are separated. The benzene layer is Washed with dilute hydrochloric acid and water until neutral, dried over anhydrous magnesium sulfate, and concentrated to dryness at reduced pressure. The residue thus obtained is recrystallized from ethyl acetate in Skellysolve B hexanes to give 6ut-methyl-4,l 6-pregnadiene-3,l1,20-trione, a light colored crystalline solid.

In the same manner substituting as the starting steroid in Preparation 2 the other pregnanes prepared and named in the second paragraph of Preparation 1 and following the procedures of Preparations 2 through 5, consecutively, there are thus produced as products of Preparation 5 the corresponding 4,16-pregnadienes as light colored crystalline solids, i.e., 2ot-methyl-4,l6-pregnadiene-3,11,20-trione, 6a-methyl 4,16 pregnadiene 3,20 dione and Zu- Inethyl-4,l6-pregnadiene-3,20-dione, respectively.

The following examples are illustrative of the processes and products of the present invention.

EXAMPLE 1A 4,16-pregnadiene-3J1,20-tri0ne 3-etlzylene ketal (II) A mixture of 31.68 g. of 4,16-pregnadiene-3,l1,20- trione (I), 500 ml. of 2-methyl-2-ethyldioxolane, and 300 mg. of p-toluenesulfonic acid monohydrate was heated to reflux for a period of about 4 hours. Water was removed during the reflux period by use of a water separator. The reaction mixture was cooled and methylene chloride was added. The methylene chloride solution was washed consecutively with sodium bicarbonate solution and water and then dried over sodium sulfate. The methylene chloride was then removed by evaporation and the resulting residue was dissolved in benzene and chromatographed on 1000 g. of acid-washed alumina. The column was eluted with increasing proportions of ether in benzene; crystalline material was obtained from the eluates containing up to 50% etherzbenzene. The crystalline material thus obtained was combined and recrystallized from acetonezSkellysolve B hexanes to give 8.5 g. of 4,16-pregnadiene-3,l1,20-trione 3-ethylene ketal melting at 228-233 C. A second crop of crystals was obtained from the mother liquors giving 1.0 g. of 4,16- pregnadiene-3,11,20-trione 3-ethylene ketal melting at 20521l C. The crystalline material was combined and recrystallized from acetonerSkellysolve B hexanes to give 4,16-pregnadiene 3,11,20 trione 3 ethylene ketal (II) melting at 233235 C.;

x3223? 234.5 m 9,500. The infrared absorption spectrum agreed with the assigned structure.

AnaIysis.-Calcd. for C H O C, 74.56; H, 8.16. Found: C, 74.43; H, 8.37.

EXAMPLE 1A 4,]6-pregnadiene-3,I],20-tri0ne 3-ethylene ketnl (11) A mixture of 195.0 g. of 4,16-pregnadiene-3,11,20- trione (I), 2 liters of benzene, 500 ml. of ethylene glycol, and g. of p-toluenesulfonic acid monohydrate was heated to reflux for a period of about 3 hours. Water was removed during the reflux period using a conventional water separator. The reaction mixture was cooled and washed with 500 ml. of saturated sodium bicarbonate solution and the benzene layer separated. The aqueous layer was extracted 3 times with benzene. The benzene extracts were combined, washed with water and dried over anhydrous sodium sulfate. The dry benzene solution was evaporated until crystallization occurred to give 44.0 g. of 4,l6'pregnadiene-3,ll,20-trione 3-ethylene ketal (II) melting at 215-230 C. The mother liquors from the crystallization were chromatographed on 2 kg. of Florisil synthetic magnesium silicate. The column was eluted with increasing proportions of acetone in Skellysolve B hexanes. The eluates containing from 7% acetonezSkellysolve B hexanes to 10% acetonezSkellysolve B hexanes gave an additional 34.3 g. of 4,16-pregnadiene3,ll,20-trione 3-ethylene ketal (II).

In the same manner, following the procedure of Examples 1A or 1A but substituting as starting material other compounds of Formula I, i.e.,

4,16-pregnadiene-3,20-dione,

2u-methyl-4,16-pregnadiene-3,l1,20-trione,

2a-methyl-4,16-pregnadiene-3 ,20-dione,

6a-rnethyl-4, l 6-pregnadiene-3 ,11,20-trione or 6cx-II16thYl-4, l 6-pr-egnadiene-3 ,20-dione,

is productive of the 3-ethylene ketals represented by Formula II, i.e.,

4,16-pregnadiene-3,20-dione 3-ethylene ketal,

2a-methyl-4,16-pregnadiene-3,l1,20-trione 3-ethylene ketal,

2ot-methyl-4,16-pregnadiene 3,ZO-dione 3-ethylene ketal,

6a-methyl-4,16-pregnadiene-3,l1,20-trione 3-ethylene ketal and 6a-methyl-4,16-pregnadiene-3,20-dione 3-ethylene ketal respectively.

EXAMPLE 2A 16a-cyano-4-pregnene-3,]1,20-tri0/ze 3-elhylene ketal (III) A mixture of 9.5 g. of 4,l6-pregnadiene-3,11,20-trione 3-ethylene ketal (II), 15.0 g. of potassium cyanide, ml. of dioxane and 500 ml. of methanol was heated in a nitrogen atmosphere under reflux for 3 hours. The reaction mixture was cooled, poured into about 2 liters of water, and extracted with methylene chloride. The methylene chloride extracts were combined, washed with water, dried over sodium sulfate and evaporated to remove the solvent. The residue thus obtained was dissolved in benzene and filtered through a column containing 20 g. of acid-washed alumina which had been previously wetted with benzene. The eluate was evaporated to remove the benzene and the residue was recrystallized from acetonezSkellysolve B hexanes to give 6.15 g. of 16a-cyano-4-pregnene-3,11,20-trione 3-ethylene ketal (III) melting at 236242 C. The product thus obtained was recrystallized twice from acetonezmethanol to give 16a-cyano-4-pregnene-3,l1,20-trione 3-ethylene ketal (III) melting at 242244 C. The infrared spectrum agreed with the assigned structure. Optical rotatory dispersion analysis indicated that the compound had the 17 fi-configuration,

Analysis.-Calcd. for C H O N: C, 72.51; H, 7.86. Found: C, 72.49; H, 7.94.

EXAMPLE 2A 1 6 ot-cyan0-4 -pregnene-3,1 1,20-zri0ne 3 -e thyl ene ketal (III) A mixture of 63.3 g. of 4,l6-pregnadiene-3,11,20-trione 3-ethylene ketal (II), 75.0 g. of potassium cyanide, 2.5 liters of methanol and 450 ml. of dioxane was heated under reflux in a nitrogen atmosphere for a period of about 3 hours. At the end of the reflux period the reaction mixture was cooled to room temperature and the solvent was removed in vacuo until crystallization occurred. Two liters of water was then added and the mixture was stirred for a few minutes; the crystalline material thus obtained was collected on a filter, washed with water and dried in vacuo at room temperature giving 47.0 g. of 16u-cyan0-4-pregnene-3,11,20- trione 3-ethylene ketal melting at 237242 C.

In the same manner, following the procedure of Example 2A or 2A but substituting as starting material other 4,16-pregnadiene 3-ethylene ketals, represented by Formula II, i.e., those listed in the second paragraph of Example 1A for 4,16-pregnadiene-3,l1,20-trione 3- ethylene ketal is productive of the corresponding 16x-cyano compound represented by Formula Ill, i.e.,

16a-cyano-4-pregnene-3,20-dione 3-ethylene ketal,

2a-methyl-16a-cyano-4-pregnene-3,11,20-trione 3-ethylene ketal,

2a-methyl-16ot-cyano-4-pregnene-3,20-dione 3-ethylene ketal,

6cx-methyl-l6a-cyano-4-pregnene-3,11,20-trione 3-ethylene ketal and 6oc-methyl-16a-cyano-4-pregnene-3,20-dione 3-ethylene ketal,

respectively.

EXAMPLE 3A 16a-cyan0-4-pregnene-3,11,20-tri0ne 3,20-bis (ethylene ketal) (IV) A mixture of 1.1 g. of 16u-cyano-4-pregnene-3,11,20- trione 3-ethylene ketal (III), 150 ml. of benzene, 3.0 ml. of ethylene glycol and 25 mg. of p-toluenesulfonic acid monohydrate was heated to boiling under reflux for a period of about 6 hours. Water was removed during the reflux period by incorporating a conventional water separator to the reflux condenser. The reaction mixture was then cooled and sodium bicarbonate solution was added. The organic layer was separated, washed with water, dried over sodium sulfate and the solvent was removed in vacuo. The residue thus obtained was recrystallized from acetonezSkellysolve B hexanes giving 640 mg. of 16a-cyano- 4-pregnene-3,11,20-trione 3,20-bis(ethylene ketal) (IV) melting at 251253 C.

In the same manner, following the procedure of Example 3A but substituting as starting material other 1600- cyano-4-pregnene 3-ethylene ketals, represented by Formula III, i.e., those listed in the second paragraph of Example 2A, for 16a-cyano-4-pregnene-3,11,20-trione 3- ethylene ketal is productive of the corresponding bis(ethylene ketal) represented by Formula IV, i.e.,

16a-cyano-4-pregnene-3,20-dione bis(ethylene ketal),

Za-methyl-16a-cyano-4-pregnene-3,l1-20-trione 3 ,20-bis (ethylene ketal),

2a-methyl-16a-cyano-4-pregnene-3,20-dione bis (ethylene ketal) 6ot-methyl-16a-cyano-4-pregnene-3,11,20-trione 3,20-bis (ethylene ketal) and 6a-methyl-16u-cyano-4-pregnene-3,20-dione bis(ethylene ketal), respectively.

EXAMPLE 4A 16u-cyan0-4-pregnene-3,11,20-lri0ne (16ot-cyan0-11ket0 progesterone) (Illa) A solution of 1.01 g. of 16a-cyano-4-pregnene-3,11,20- trione 3-ethylene ketal (III) in acetone containing ml. of water and 3 drops of sulfuric acid was allowed to stand for a period of about 18 to 24 hours at room temperature. Sodium bicarbonate solution was then added and the acetone was removed in vacuo at room temperature until crystallization commenced. An additional 100 ml. of water was then added, the temperature of the mixture was lowered to 0 C. and crystallization was allowed to proceed. The solid material was collected by filtration, dried, and crystallized twice from acetonezSkellysolve B hexanes to give 500 mg. of l6oc-CY8HO-4-PICgmeme-3,1 1,20-t1'i0ne melting at 230-235 C. A final cryso2 tallization from methanol raised the melting point to 238240 C.,

Eton Mm.

16m-cyano-4-pregnene-3 ,ZO-dione, 2a-methyl-16a-cyano-4-pregnene-3 ,11,20-trione, Zu-methyl- 1 6u-cyano-4-pregnene-3 ,20-dione, 6a-methyll 6oc-cyano-4-pregnene-3 ,1 1,20-trione and 6oc-melll'lyl-l6a-CY211'10-4-pregnen6-3 ,2 O-dione,

respectively.

EXAMPLE 5A 16a-carb0xy-4-pregnene-3,11,20-tri0ne 3,20 bis(ethylene ketal) (V) and l6ot-carbometh0xy-4-pregnene-3,I1,20- trione 3,20-bis(ethylene ketal) (V) A mixture of 13.7 g. of l6ct-cyano-4-pregnene-3,11,20- trione 3,20-bis(ethylene ketal) (IV), 400 ml. of ethylene glycol and 25 g. of potassium hydroxide dissolved in ml. of water was heated to reflux in a slow stream of nitrogen for a period of about 20 to 24 hours. After cooling, water was added and the alkaline solution was extracted with methylene chloride. The aqueous layer was then cooled to 0 C., carefully acidified to about pH 4 and rapidly extracted with ethyl acetatezmethylene chloride. The combined ethyl acetate:methylene chloride extracts were washed with water until neutral, dried over sodium sulfate and the solvent removed by evaporation to give a residue comprising carboxy 4 pregnene- 3,11,20-trione 3,20-bis(ethylene ketal) melting at 225- 245 C. which can be purified by either chromatography or crystallization or both to give 16oc-carboxy-4-pregnene- 3,11,20-tri0ne, a crystalline solid.

The residue thus obtained was dissolved in 200 ml. of methylene chloride and 500 ml. of methanol and esterified with excess ethereal diazomethane solution for 3 hours at room temperature. The solvent was removed by evaporation and the residue thus obtained was crystallized from acetone:Skellysolve B hexanes to give 9.8 g. of 16a-carbomethoxy-4 pregnene 3,11,20 trione 2,20 bis(ethylene ketal) melting at about 200 C. Two recrystallizations from the same solvent gave 16ot-carbomethoxy-4-pregnene-3,11,20-trione 3,20-bis(ethylene ketal) (V) melting at 224-225 C. The infrared spectrum agreed with the assigned structure.

Alzalysis.Calcd. for C H O C, 68.33; H, 8.07. Found: C, 68.29; H, 7.94.

In the same manner, following the procedure of Example 5A but substituting as starting material other 160:- cyano-4-pregnene 3,20-bis(ethylene ketals) represented by Formula IV, i.e., those listed in the second paragraph of Example 3A for 16ot-cyano-4-pregnene-3,11,20-trione 3,20-bis(ethylene ketal), hydrolysis with potassium hydroxide is productive of the corresponding 16a-carboxy compound represented by Formula V, i.e.,

16ot-carboxy-4-pregnene-3,20-dione bis(ethylene ketal),

Za-methyl-l6ot-carboxy-4-pregnene-3,11,20-trione 3,20- bis (ethylene ketal) 2tx-methyl-16otcarboxy-4-pregnene-3,20-dione bis (ethylene ketal) 6a-methyl-16a-carboxy-4-pregnene-3,1 1,20-trione 3,20-

bis(ethylene ketal), and

33 Ga-methyl-16u-carboxy-4-pregnene-3,ZO-dione bis (ethylene ketal),

respectively, all crystalline solids.

The 16a-carboxy compounds thus produced can be esterified with ethereal diazomethane solution in the same manner to give the corresponding 160L-C21Ib0IIlEtl'lOXY compounds represented by Formula V, i.e.,

16a-carbomethoxy-4-pregnene 3,20-diorie bis(ethylene ketal),

2a-methyl-16a-carbomethoxy-4-pregnene-3,11,20-trione 3,20-bis (ethylene ketal) 2a-methyl-16a-carbomethoxy-4-pregnene 3,20-dione bis (ethylene ketal),

Got-methyl-16u-carbomethoxy-4-pregnene-3,11,20-trione 3,20-bis (ethylene ketal), and

6u-methyl-16u carbomethoXy-4-pregnene-3,20-dione bis (ethylene ketal),

respectively.

EXAMPLE 6A I 1 fi-hydroxy-I 6 a-hydroxymethy l-4-pregnene-3 ,1 d ione bis (ethylene ketal) (VI A solution of 9.7 g. of 16a-carbomethoxy-4-pregnene- 3,11,20-trione 3,20-bis(et hylene ketal) (V) in benzene was added at 0 C. to a stirred suspension of 12.0 g. of lithium aluminum hydride in 150 ml. of ether and 150 ml. of benzene. The mixture was heated under reflux for a period of about 4 hours and then cooled in an icewater bath. The excess lithium aluminum hydride was decomposed by the addition of ethyl acetate and then water. The reaction mixture was then filtered and the organic layer was separated, washed with water and the solvent was removed by evaporation. The crude residue thus obtained was crysallizted from ethyl acetate:Skellysolve B hexanes to give 2.4 g. of 11,8-hydroxy-16a-hydroxymethyl-4-pregnene-3,-20-dione bis (ethylene ketal) (VI) melting at 195-205 C. A second crop of crystals from the mother liquors gave an additional 0.3 g. Recrystallization from acetonezSkel-lysolve B hexanes gave 11/3 hydroxy 16a hydroxymethyl 4 pregnene-3,20 dione bis (ethylene ketal) melting at 209-21l C. Chromatography of the mother liquors on Florisil synthetic magnesium silicate and elution with 20% acetonezSkellysolve B h'exanes gave an additional 0.79 g. of lle-hydroxy 160: hydroxymethyl 4 pregnene 3,20 dione bis(ethylene ketal) melting at 195-205 C. The infrared spectrum supported the assigned structure.

Analysis.Calcd. for C H O C, 69.61; H, 8.99. Found: C, 69.61; H, 8.61.

In the same manner, following the procedure of Example 6A but substituting other 16a-carbomethoxy-4- pregnene 3,20-bis(ethylene ketals), represented by Formula V, i.e., those listed in the fourth paragraph of Example SA, for 16-carbomethoXy-4-pregnene-3,11,20-trione 3,20-bis(ethylene ketal) is productive of the corresponding 16oz hydroxymethyl 4 pregnene 3,20 dione bis(ethylene ketal) represented by Formula VI, i.e.,

l6a-hydroxymethyl-4-pregnene-3,20-dione bis (ethylene ketal),

2a-methy1-1 1fl-hydroxy-16a-hydroxymethy1-4-pregnene- 3,20-dione bis (ethylene ketal) 2u-methyl-16ahydroxymethyl-4pregnene-3,20-dione bis- (ethylen'e ketal) 6a-methy1-1 1,B-hydroxy-16a-hydroXyrnethyl-4-pregnene- 3,20-dione bis(ethylene ketal),

and 6arnethyl-16et-hydroXymethyl-4-pregnene-3,20-dione bis(ethylene ketal),

respectively.

EXAMPLE 6A 1IB-hydroxy-l6ot-hydroxymethyl-4-pregene-3,20- dione bis(ethylene ketal) VI) A mixture of 5.08 g. of 16a-carboxy-4-pregnene-3,11, 20-trione 3,20-bis(et'hylene ketal) and 3.5 g. of lithium aluminum hydride in 350 ml. of tetrahydrofuran was refluxed for a period of about 3 hours. The bisketal was introduced into the reaction mixture employing the Soxhlet technique. The reaction mixture was cooled and the excess lithium aluminum hydride was decomposed by the addition of ethyl acetate and then water followed by filtration to remove the inorganic salts. The organic layer was separated, washed with water and evaporated in vacuo to remove the solvent. The residue thus obtained was crystallized from acetone: methanol to give 3.9 g. of 1lfi-hydroxy-l6ot-hydroxymethyl-4-pregnene-3, 20-dione bis(ethylene ketal) (VI).

In the same manner, following the procedure of EX- ample 6A' but substituting other 16ot-carboxy-4-pregnene 3,20-bis(ethylene ketals), represented by Formula V, i.e., those listed in the third paragraph of Example 5A for 16 carbomethoxy 4 pregnene 3,11,20 trione 3,20- bis(ethylene ketal) is productive of the corresponding 16a-hydroxymethyl-4-pregnene-3,20 dione bis(ethylene ketal) represented by Forurnla VI, i.e.,

16 x-hydroXymethyl-4-pregnene-3,20dione bis(ethylene ketal),

2tx-m'ethyl-1 1 ,e-hydroxy-l 6u-hydroXymethyl-4-pregnene- 3,20-dione bis(ethylene ketal),

2u-methyl-16a-hydroxymethyl-4pregnene-3,ZO-dione bisethylene ketal),

6a-methyl-1 lB-hydroxy-16a-hydroxymethyl-4-pregnene- 3,20-dione bis(ethylene ketal), and

6u-methyl-16ot-hydroxymethyl-4pregnene-3,20-dione bis- (ethylene ketal),

respectively.

EXAMPLE 7A 1 1 fi-hydroxy-I 6a-aceloxymelhyl-4-pregnene-3,20- dione bis(ethylene ketal A solution of 1.0 g. of 11 8-hydroXymethyl-4-pregnene- 3,20-dione bis(ethylene ketal) (VI) in 5' ml of acetic anhydride and 5 ml. of pyridine is allowed to stand at room temperature until the acylation is complete. The reaction mixture is then poured into ml. of ice-water and the resulting aqueous mixture is extracted with three 25 ml. portions of methylene chloride. The extracts are combined, washed with water, dried over sodium sulfate and evaporated in vacuo to remove the solvent. The residue thus obtained is recrystallized from acetonezSkellysolve B hexanes to give 1Iii-hydroxy-Met-acetoxymethyl-4-pregnene-3,20-dione bis(ethylene ketal).

In the same manner following the procedure of Example 7A but substituting as starting material other 11 fl-hydroxy compounds represented by Formula VI, and prepared in Example 6A, above, i.e., 2a-met-hyl-llfihydroxy-l6 a-hydroxymethyl-4-pregnene-3,20 dione bis (ethylene ketal) or 604 methyl 11,8 hydroxy 16oz hydroxymethyl 4- pregnen'e-3,20-dione bis(ethylene ketal) for llfl-hydroxy- 16oz hydroxymethyl 4 pregnene 3,20 dione bis(ethylene ketal) is productive of lot-methyl-l1B-hydroXy-16aacetoxymethyl-4-pregnene-3,20-dione bis(ethylene ketal) and 6a methyl 11B hydroxy 16a acetoxymethyl 4- pregnene-3,20- dione bis(ethylene ketal), respectively.

EXAMPLE 8A l6ot-trcetoxymelhyl-4-pregnene-3,11,20-tri0ne 3,20- bis(ethylene ketal) A mixture of 300 mg. of 11B-hydroXy-16u-acetoxymethyl-4-pregnene-3,20-dione bis(ethylene ketal) in 5 ml. of pyridine is added to a suspension of chromium trioxide: pyridine complex (prepared from 300 mg. of chromium trioxide and 5 ml. of pyridine). The reaction mixture is allowed to stand at room temperature for a period of about 18 to 24 hours. Water and benzene:ether (1:1) is then added and the mixture is stirred thoroughly and then filtered through Supercel diatomaceous earth. The organic layer is separated, washed with water, dried over sodium sulfate and evaporated to remove the solvent, giving crude 16a .acetoxymethyl 4 pregnene 3,11,20- trione 3,20-bis(ethylene ketal). The crude product is recrystallized from acetonezSkellysolve B hexanes to give 16a acetoxymethyl 4 pregnene 3,11,20 trione 3,20- bis(ethylene ketal), a crystalline solid. Alternatively, if desired, the residue may be purified by chromatography.

In the same manner following the procedure of Example 8A, but substituting as starting material 2a-methyl- 11,8 hydroxy 16a acetoxymethyl 4 pregnene 3,20- dione bis(ethylene ketal) or 6u-methyl-1lfi-hydroxy-lcxacetoxymethyl-4-pregnene-3,20-dione bis(ethylene ketal) prepared in Example 7A above, for 11B-hydroxy-16otacetoxymethyl 4 pregnene 3,20 dione bis(ethylene ketal) is productive of Za-methy-l-l6u-acetoxyrnethyl-4- pregnene 3,11,20 trione 3,20(ethylene ketal) and 60C- methyl 16cc acetoxymethyl 4 pregnene 3,11,20-trione 3,20-bis(ethylene ketal), respectively.

EXAMPLE 9A 16a-hydr0xymethyl-4-pregnene-3,11,20-tri0ne 3,20-bz's(ethylene ketal) (Vla) To 1.0 g. of 16ot-acetoxymethyl-4-pregnene-3,11,20- trione 3,20-bis ethylene ketal) in 15 ml. of methanol is added ml. of a 25 percent solution of sodium hydroxide in aqueous methanol. The reaction mixture is stirred in a nitrogen atmosphere and then allowed to stand overnight at room temperature. The reaction mixture is then diluted with 100 ml. of water, neutralized with dilute acetic acid and extracted three times with methylene chloride. The methylene chloride extracts are combined, Washed with sodium bicarbonate solution and water, dried over sodium sulfate and evaporated at reduced pressure to remove the solvent. The residue thus obtained is recrystallized from acetone: Skellysolve B hexanes to give 16a-hydroxymethyl-4-pregnene-3,11,20 trione 3,20 bis (ethylene ketal) (VIa) a crystalline solid. Alternatively, if desired, the residue may be purified by chromatography.

In the same manner following the procedure of Example 9A, but substituting as starting material Za-methyl- 16a-acetoxymethyl-4-pregnene 3,11,20 trione 3,20 bis (ethylene ketal) or 6a-methyl-16ot-acetoxymethyl-4-pregnene-3,11,20-trione 3,20-bis(ethylene ketal) prepared in Example 8A, above, is productive of Za-methyl- 1 6a-hydroxymethyl-4-pregnene-3 ,1 1,20-

trione 3,20-bis(ethylene ketal) (Vla) and 6a-methyl-16a-hydroxymethyl-4-pregnene-3 ,1 1,20-trione 3,20-bis(ethy1ene ketal) (VIa), respectively.

EXAMPLE 10A 1 1 fl-hydroxy-I 6 ot-hydroxym'elhyl-4 -pregner1e- 3,20-di0ne (VIb) To a solution of 300 mg. 11fi-hydroxy-160t-hydroxymethyl-4-pregnene-3,20-dione bis(ethylene ketal) (VI) in acetone containing 10% by volume of water was added 1 ml. of percent sulfuric acid. The mixture was boiled for a period of about 10 minutes and then allowed to stand at room temperature to complete the hydrolysis. At the end of the reaction period excess sodium bicarbonate solution was added and the acetone was removed in vacuo at room temperature until crystallization commenced. An additional 50 ml. of water was added, and crystallization was allowed to proceed at 0 C. The crystalline material was then collected by filtration and dried in vacuo to give 150 mg. of llfi-hydroxy- 16a hydroxymethyl 4 pregnene-3,20-dione melting at 234238 C. Recrystallization from acetonezSkellysolve B hexanes gave 1lfl-hydroxy-l6a-hydroxymethyl-4-pregnene-3,20-dione melting at 244246 C.,

XEtOH 24:2 mp.

Analysis.Calcd. for C H O C, 73.30; H, 8.95. Found: C, 73.24; H, 9.35.

In the same manner following the procedure of Example 10A but substituting as starting material other 3,20-bis(ethylene ketals) represented by Formulae VI and VIa and prepared in Examples 6A and 9A, i.e., 16at-hydroxymethyl-4-pregnene 3,20 dione bis(ethylene ketal), 16ot-hydroxymethyl-4-pregnene-3,1 1,20-trione 3,20-bis (ethylene ketal),

Za-methyl-l 1 B-hydroxy- 1 6ot-hydroxymethyl-4-pregnene- 3,20-dione bis(ethylene ketal),

2a-methyl-16ot-hydroxymethyl-4-pregnene-3,20-dione bis(ethylene ketal),

Za-methyl-16a-hydroxymethyl-4-pregnene-3,1 1,20-trione 3,20-bis(ethylene ketal),

60t-Ill6thYi-1 1 B-hydroxy- 1 6a-hydroxymethyl-4-pregnene- 3,20-dione bis(ethylene ketal),

6a-methyl-16ot-hydroxymethyl-4-pregnene-3,20-dione bis(ethylene ketal) and 6a-methyl-16a-hydroxy-methyl-4-pregnene-3 ,1 1,20-

trione 3,20-bis(ethylene ketal) for 115 hydroxy 16a hydroxymethyl-4-pregnene3,20- dione bis(ethylene ketal) is productive of other compounds represented by Formula VIb, i.e., 16ot-hydroxymethyl-4-pregnene-3,20-dione, 16a-hydroxymethyl-4-pregnene-3,11,20-trione, 2ot-methyl-1 lfi-hydroxy-16ot-hydroxymethyl-4-pregnene- 3,20-dione, Za-methyI-I6ot-hydroxymethyl-4-pregnene-3,ZO-dione, 2a-methyl-16a-hydroxymethyl-4-pregnene-3 ,l l,20-trione, 6ot-methyl-1 lfl-hydroxy-16ahydroxymethyl-4-pregnene- 3,20-dione, 6ot-methyl-16ot-hydroxymethyl-4-pregnene-3,20-dione and 6u-methyl-16ot-hydroxymethyl-4-pregnene-3 ,1 1,20-trione,

respectively.

EXAMPLE 11A 16ot-flu0r0methyl-11fl-hydroxy-4-pregnene-3,20-di0ne bis(ethylene ketal) (VIII) A solution of 1.0 g. of 11fi-hydroxy-16a-hydroxymethyl-4-pregnene-3,ZO-dione bis(ethylene ketal) (VI) and 1.0 g. of p-toluenesulfonyl chloride in pyridine is allowed to stand for a period of about 18 to 24 hours at room temperature. The reaction mixture is then poured into ice water and extracted with methylene chloride. The combined methylene chloride extracts are washed consecutively with sodium bicarbonate solution and water and dried over sodium sulfate. The methylene chloride is then removed by evaporation giving crude 11 fi-hydroxy- 16a (p toluenesulfonyloxymethyl) 4 pregnene 3,20- dione bis(ethylene ketal) (VII). The crude 11,8-hydroxy 16cc (p toluenesulfonyloxymethyl) 4 pregnene-3,20-dione bis(ethylene ketal) is dissolved in about 25 ml. of redistilled diethylene glycol and heated with 2.4 g. of anhydrous potassium fluoride at 200210 C. for about 1 hour under an atmosphere of nitrogen. The reaction mixture is then cooled, poured into water and extracted with ethyl acetate. The extracts are combined, washed with water, and dried over sodium sulfate. The solvent is then removed by evaporation giving a crude residue containing 116 hydroxy 16oz fluoromethyl-4- pregnene-3,20-dione bis(ethylene ketal). The crude residue is dissolved in methylene chloride, chromatographed on g. of Florisil synthetic magnesium silicate and eluted with increasing proportions Of acetone in Skellysolve B hexanes. The solvent is evaporated from each of the fractions and those containing crystalline material are combined and recrystallized from acetonetSkellysolve B hexanes to give 1lfi-hydroxy-16ot-fluoromethyl-4-pregnene-3,20-dione bis(ethylene ketal) (VIII) melting at 183185 C. The infrared spectrum is in agreement with the structure.

Analysis.Calcd. for C H FO C, 69.34; H. 8.67; F, 4.22. Found: C, 69.61; H, 9.03; F, 3.74.

In the same manner, following the procedure of Example 11A but substituting other l6oc-hydroxymethyl-4 pregnene-3,20-dione bis(ethylene ketals), represented by Formula VI, i.e., those listed in the second paragraph of Example 6A for 1lp-hydroxy-l6a-hydroxymethyl-4- pregnene-3,20-dione bis(ethylene ketal) is productive of the corresponding 16a-(patoluenesulfonyloxymethyl)-4- pregnene-3,20-dione bis-(ethylene ketal) represented by Formula VII, i.e.,

161x-(p-toluenesulfonyloxymethyl) -4-pregnene,3 ,20-

dione bis(ethylene ketal) 2a-rnethyl-1 1,8-hydroxy16x- (p-toluenesulfonyloxymethyl)-4-pregnene-3,20-dione bis(ethylene ketal),

Zoe-methyl-16a-(p-toluenesulfonyloxymethyl)-4- pregnene3 ,ZO-dione bis ethylene ketal) 6u-methyl- 1 1fl-hydroxy-16a- (p-toluenesulfonyloxymethyl)-4-pregnene-3,20-dione bis(ethylene ketal) and 6tx-methyl-16a-(p-toluenesulfonyloxymethyl)-4-pregnene- 3,20-dione bis(ethylene ketal) respectively. The 16a (p toluenesulfonyloxymethyl) compounds thus produced are converted to the corresponding 16a-fluoromethyl compounds (VIII) with anhydrous potassium fluoride in the same manner as in Example 11A to give 16a-fluoromethyl-4-pregnene-3 ,20-dione bis ethylene ketal) Za-methyl-l 1 fi-hydroxy-l6a-fiuoromethyl-4-pregnene- 3,20-dione bis(ethylene ketal) 2tx-methyl16ctfluoromethyl-4-pregnene-3,20-dione bis(ethylene ketal) 3,20-dione bis(ethylene ketal) and 6o -methyl-16a-fluoromethyl-4-pregnene-3,20'dione bis(ethylene ketal) respectively.

In the same manner, following the procedure of Example 11A but substituting as the starting steroid the ll-keto compounds represented by Formula VIa prepared in Example 9A and the paragraph following Example 9A is productive of the corresponding 16x-p-toluenesulfonyloxymethyl derivatives (VII) which are then converted with potassium fluoride to the corresponding 11- keto-l6a-fiuoromethyl compounds (VIII), i.e.,

16a-fluoromethyl-4-pregnene-3,1 1,20-trione 3,20-bis (ethylene ketal),

2m-methyl-16o-fluoromethyl-4-pregnene-3,1 1,20-trione 3,20-bis(ethylene ketal) and a-methyl-16afluoromethyl-4-pregnene-3 ,11,20trione 3,20-bis(ethylene ketal) respectively.

EXAMPLE 12A 1IB-hydroxy-I6a-flu0r0methyl-4-pregnene-3,20- dione (IX) To a solution of 300 mg. l1fi-hydroxy-16tx-fiuoromethyl-4-pregnene-3,20-dione bis(ethylene ketal) (VIII) in acetone containing by volume of water is added 1.0 ml. of 25 percent sulfuric acid; the solution is boiled for about 10 minutes and then allowed to stand at room temperature until hydrolysis is complete. At the end of the reaction excess sodium bicarbonate solution is added and the acetone is removed in vacuo at room temperature until crystallization commences. An additional 50 ml. of water is then added and the crystallization is allowed to proceed at 0 C. The solid material thus obtained is collected by filtration, washed with water and dried in vacuo to give 1lfi-hydroxy-l6u-fluoromethyl4- pregnene-3,20-dione, a crystalline solid. The product can be further purified by recrystallization from acetone: Skellysolve B hexanes.

In the same manner following the procedure of Example 12A, but substituting as starting material other 16a fiuoromethyl 4-pregnene 3,20-dione bis(ethylene ketals) represented by Formula VIII, i.e., the 16a-fluoromethyl compounds prepared and listed in the second and third paragraphs of Example 11A for 1lfi-hydroxy-16afluoromethyl 4 pregnene-3,20-dione bis(ethylene ketal) is productive of the corresponding hydrolyzed compound (IX), i.e.,

16a-fiuoromethyl-4-pregnene-3 ,20-dione,

Za-methyl-l 1B-hydroxy-16ot-fluoromethyl-4-pregnene- 3,20-dione,

Za-methyl-16a-fluoromethyl-4-pregnene-3 ,20-dione,

6a-methyl-1 1fi-hydroxy-16a-fluoromethyl-4-pregnene- 3 ,20-dione,

Gu-methyl-16ot-fiuoromethyl-4-pregnene-3 ,2.0-dione,

l6ot-fluoromethyl-4-pregnene-3 ,11,20-trione,

Za-methyl-16a-fiuoromethyl-4-pregnene-3 ,1 1,20-trione and 6u-methyl-16a-fluoromethyl-4-pregnene-3 ,11,2()-trione,

respectively.

EXAMPLE 13A 16a-flu0r0methyl-4-pregIwne-3J1,20-trione (IX) A mixture of 280 mg. of 115 hydroxy 16a-fiuoromethyl-4-pregnene-3,20-dione bis(ethylene ketal) (VIII) and 5 ml. of pyridine is added to a suspension of chromium trioxidezpyridine complex (prepared. from 300 mg. of chromium trioxide and 5 ml. of pyridine). The reaction mixture is allowed to stand at room temperature until the oxidation is completed. Water and benzene: ether (1:1) are then added. The mixture is stirred thoroughly and filtered through Supercel diatomaceous earth. The organic layer is separated, washed with water, dried over sodium sulfate and evaporated to remove the solvent. The residue thus obtained, containing 1604- fluor-omethyl 4 pregnene 3,11,20-trione bis(ethylene ketal) is dissolved in 50 ml. of acetone and 5 ml. of water and hydrolyzed by standing at room temperature for a period of about 30 hours with 0.5 ml. of 25% sulfuric acid. At the end of the reaction excess sodium bicarbonate solution is added and the acetone is removed in vacuo at room temperature, until crystallization commences. An additional ml. of water is then added and the crystallization is allowed to proceed at 0 C. The crystalline solid is collected by filtration, washed with water and dried to give crude 16a-fluoromethyl-4- pregnene-3,11,20-trione. The crude product thus obtained is recrystallized twice from acetonezSkellysolve B hexanes to give l6ot-fluoromethyl-4-pregnene-3,11,20- trione (IX) melting at 223-226" C.

In the same manner following the oxidation procedure of Example 13A, but substituting as starting material 20: methyl 11,6 hydroxy-16a-fluoromethyl-4-pregnene-3,20-

dione bis(ethylene ketal) (VIII) or 6e-methyl-11B-hydroxy-16a-fiuoromethyl-4-pregnene-3,20-dione bis(ethylene ketal) (VIII) (prepared in Example 11A) for hydroxy 16a fiuoromethyl-4-pregnene-3,20-dione bis (ethylene ketal) is productive of 2a-methyl-16a-iluoromethyl 4 pregnene 3,11,20-trione 3,20-bis(ethylene ketal) and 6ot-methyl-16wfiuoromethyl-4-pregnene-3,11, ZO-trione 3,20bis(ethylene ketal), respectively, which when subjected to hydrolysis according to the procedure of Example 13A is productive of 2a-methyl-16a-fluoromethyl-4-pregnene-3,11,20-trione (IX) and 6a-methyl- 16a fluoromethyl 4-pregnene-3,11,20-trione (IX), respectively.

EXAMPLE 14A Su-hydrOxy-J6u-cyan0-5fi-pregnane-11,20-di0ne (A-II) A mixture of 20.0 g. of 3a-acetoxy-l6-pregnane-11,20- dione (A-I), 30.0 g. of potassium cyanide, 1 liter of methanol and 200 ml. of dioxane was heated to boiling under reflux for a period of 3 hours. At the end of the reflux period the reaction mixture was cooled, water was added and the organic material was extracted with methylene chloride. The combined extracts were washed with water, dried over sodium sulfate and evaporated to remove the solvent. The crystalline residue thus obtained was recrystallized from acetonezSkellysolve B hexanes to give 9.5 g. of 3a-hydroxy-16a-cyano-5fl-pregnane-l1,20- dione melting at 222226 C. Further recrystallization from acetonezSkellysolve B hexanes gave 3OL-hYdIOXY-160tcyano-Sfi-pregnane-l1,20-dione (AII) melting at 238- 240 C.; the infrared spectrum agreed with the assigned structure and optical rotatory dispersion analysis indicated the Vii-configuration.

Analysis.Calcd. for C H O N: C, 73.91; H, 8.74; N, 3.92. Found: C, 74.34; H, 9.04; N, 4.11.

EXAMPLE 15A 3ot-hydr0xy-16a-cyan0-5fi-pregnane-11,20-di0ne ZO-elhylene ketal (A-III) A mixture of 5.5 g. of 3ot-hydroxy-l 6a-cyano-5fi-pregnane-11,20-dione (A-II), 25 ml. of ethylene glycol, 250 mg. of p-toluenesulfonic acid monohydrate and 500 ml. of benzene was heated to reflux for a period of 6 hours. Water was removed during the reflux period by use of a conventional water separator. The reaction mixture was then cooled in an ice-water bath and saturated aqueous sodium bicarbonate solution was added. The benzene layer was separated and the aqueous layer was extracted with additional benzene. The combined benzene extracts were washed with water until neutral, dried over sodium sulfate and evaporated to remove the solvent. The oil thus obtained was dissolved in methylene chloride and chromatographed on 300 g. of Florisil synthetic magnesium silicate which had been pre-treated with Skellysolve B hexanes. The column was eluted with increasing proportions of acetone in Skellysolve B hexanes. The solvent was removed from the eluates by evaporation. Crystalline material was obtained from the fractions eluted with 20% acetonezSkellysolve B hexanes. These fractions were combined and recrystallized from ether to give 3.25 g. of 3 u-hydroxy-16a-cyano-5fl-pregnane-1 1,20-dione 20-ethylene ketal melting at 164170 C. A second crop of crystals was obtained from the mother liquors giving an additional 0.54 g. of 3ot-hydroxy-16ot-cyano-5fi-pregnane- 11",20-dione 20-ethylene ketal. Further recrystallization from ether gave 3a-hydroxy-16a-cyano-5p-pregnane-l 1,20- dione 20-ethylene ketal (A-III) melting at 168-170" C. The infrared spectrum confirmed the structure.

Analysis.Calcd. for C H O.,N: C, 71 .79; H, 8.79; N, 3.49. Found: C, 71.12; H, 8.67; N, 3.68.

EXAMPLE 16A 3ot-hydr0xy-1 61x-carbomethoxy-SB-pregnane-I1,20 dione ZO-ethylene ketal (A-IV) A solution of 2.85 g. of 3a-hydroxy-16a-cyano-5/3- pregnane-11,20-dione 20-ethylene ketal (A-III) and 5.0 g. of potassium hydroxide in 80 ml. of ethylene glycol and 20 ml. of water was heated to boiling under reflux in a nitrogen atmosphere for a period of 24 hours. The solution was then cooled, diluted with about 250 ml. of water and extracted twice with methylene chloride. The aqueous layer was then carefully acidified to about pH 4, first with sodium dihydrogen phosphate and then with ice cold dilute hydrochloric acid, and rapidly extracted with ethyl acetate. The combined ethyl acetate extracts were washed with water until neutral, dried over sodium sulfate and evaporated in vacuo to remove the solvent. The residue thus obtained was dissolved in 250 ml. of methanol and 250 ml. of methylene chloride and esterified with excess ethereal diazomethane at room temperature for a period of '3 hours. The solvent was then removed by evaporation in vacuo. The residual oil thus obtained was dissolved in acetone:Skellysolve B hexanes and crystallized to give 2.21 g. of 3a-hydroxy-16a-carbornethoxy-SB-pregnane- 11,20-dione 20-ethylene ketal melting at 221-223 C. Further recrystallization gave 3a-hydroxy-16a-carbomethoxy-Sfl-pregnane-l1,20-dione-ethylene ketal (AIV) melting at 222223 C. The infrared spectrum supported the structure.

Analysis.Calcd. for C H O C, 69.09; H, 8.81. Found: C, 69.29; H, 8.89.

EXAMPLE 17A 16acarb0methoxy-Sfi-pregnane-3,11,20 trione 3,20 bis (ethylene ketal) (A-V) A solution of 2.05 g. of 30t-hYdIOXY-160t-CEIIbOI'I16lhOXY- 5.,8-pregnane-11,20-dione 20-ethylene ketal (A1V) in 200 ml. of acetone was oxidized for 510 minutes at 0 C. with 1.85 ml. of standard chromium trioxidezsu'lfuric acid reagent (prepared by dissolving 26.72 g. of chromium trioxide in 25 ml. of concentrated sulfuric acid and diluting with water to ml.). Saturated aqueous sodium bicarbonate solution was then added to the reaction mixture followed by filtration through Supercel diatomaceous earth. The filtrate was extracted with methylene chloride and the combined extracts were washed with water, dried over sodium sulfate and evaporated to remove the solvent. The residual oil thus obtained was dissolved in acetone: Skellysolve B hexanes and crystallized to give 1.73 g. of 16a-carbomethoxy 55 pregnane 3,11,20 trione 20- ethylene ketal melting at 154 to 156 C.

A mixture of 1.68 g. of 16u-carbomethoxy-5fi-pregnane-3,ll,20-trione 20-ethylene ketal, 10 ml. of ethylene glycol, 1 50 mg. of p-toluenesulfonic acid monohydrate and 200 ml. of benzene was heated to reflux incorporating a water separator for a period of 16 hours. The reaction mixture was then cooled and sodium bicarbonate solution was added. The organic layer was separated from the aqueous layer, washed with water, dried over sodium sulfate and evaporated to remove the solvent. The residue, thus obtained, was crystallized from acetonezSkellysolve B hexanes to give 1.74 g. of 16tx-carbornethoxy-5fipregnane-3,11,20-trione 3,20-bis(ethylene ketal) (AV) melting at 200-225 C. The infrared spectrum supported the assigned structure.

Analysis.Calcd. for C H O C, 68.04; H, 8.46. Found: C, 67.74; H, 8.48.

EXAMPLE 18A 1 1,B-hydroxy-Idot-hydroxymethyl-Sfi-pregnane-3,20-di0ne bis(ethylene ketal) (A-VI) A solution of 1.6 g. of 16ot-carbomethoxy-SB-pregnane- 3,11,20-trione 3,20-bis(ethylene ketal) in 50 ml. of henzene was added dropwise to a stirred suspension of 2.0 g. of lithium aluminum hydride in 30 ml. of diethyl ether and 20 ml. of benzene keeping the temperature at 0 C. or below. The mixture was then heated under reflux for a period of about 4 hours. The reaction mixture was cooled and the excess hydride was decomposed with ethyl acetate followed by about 5 ml. of water. The organic layer was then filtered with the aid of Supercel diatomaceous earth. The filtrate was washed with Water, dried over sodium sulfate and evaporated to remove the solvent giving 1.605 g. of crude product which when crystallized from acetonezSkellysolve B hexanes gave 1.18 g. of 11,8- hydroxy-16oc-hydroxymethyl-SB-pregnane-3,20 dione bis (ethylene ketal) melting at 196203 C. Two recrystallizations from acetone:Skellysolve B hexanes gave 11;?- hydroxy-l6ot-hydroxyrnethyl-5fi-pregnane-3,20 dione bis (ethylene ketal) (A-VI) melting at 204205 C. The infrared spectrum supported the assigned structure.

Analysis.Calcd. for C H O C, 69.30; H, 9.40. Found: C, 69.53; H, 9.41. 

1. A COMPOUND SELECTED FROM THE FORMULAE: 